Is tuberous sclerosis complex-associated autism a preventable and treatable disorder?

Inhibition of p70 Ribosomal S6 Kinase (S6K1) Reduces Cortical Blood Flow in a Rat Model of Autism-Tuberous Sclerosis

“…Previously, we reported no significant effects resulting from the stimulation or blockade of AMPA receptors (Weiss et al, 2009 , 2012 ), GABA A receptor blockade (Weiss et al, 2008 ), or NMDA receptor blockade (Weiss et al, 2007 ) on the elevated regional cerebral blood flow (rCBF) in Eker rats. In TSC and ASD, an elevated excitation/inhibition balance has been proposed as one of the causes for seizures and autism-like behavior (Bassetti et al, 2021 ; Curatolo et al, 2022 , 2023 ; Mizuguchi et al, 2021 ; Rubenstein & Merzenich, 2003 ). Vigabatrin, an inhibitor of GABA transaminase and a modulator of excitation/inhibition balance, has been employed clinically and in animal models to alleviate seizures and ASD (Bombardieri et al, 2010 ; Curatolo et al, 2022 , 2023 ; Specchio et al, 2023 ).…”

“…In TSC and ASD, an elevated excitation/inhibition balance has been proposed as one of the causes for seizures and autism-like behavior (Bassetti et al, 2021 ; Curatolo et al, 2022 , 2023 ; Mizuguchi et al, 2021 ; Rubenstein & Merzenich, 2003 ). Vigabatrin, an inhibitor of GABA transaminase and a modulator of excitation/inhibition balance, has been employed clinically and in animal models to alleviate seizures and ASD (Bombardieri et al, 2010 ; Curatolo et al, 2022 , 2023 ; Specchio et al, 2023 ). Notably, vigabatrin is known to reduce CBF and glucose metabolism in epilepsy patients (Hosking et al, 2003 ; Spanaki et al, 1999 ).…”

“…Tuberous sclerosis complex (TSC) is a genetic disorder marked by the formation of multiple benign tumors arising from mutations in TSC1 or TSC2 genes. Epilepsy is the most common sign of human TSC (about 90%) followed by autism spectrum disorders (ASD) (50%) and intellectual disability (45%) (Curatolo et al, 2023 ; Henske et al, 2016 ; Peters et al, 2013 ). TSC protein complexes that include TSC1 and TSC2 function as inhibitors of the mammalian target of rapamycin (mTOR) signaling pathway (Curatolo et al, 2022 ; Huang & Manning, 2008 ).…”

“…The Eker rat, carrying a spontaneous germline mutation in TSC2 gene ( Tsc2 ±) (Curatolo et al, 2022 , 2023 ; Henske et al, 2016 ; Peters et al, 2019 ), has been an invaluable model for understanding TSC (Habib, 2010 ; Kútna et al, 2020 ; Wenzel et al, 2004 ). Research has demonstrated that this animal model exhibits comparable molecular defects observed in other mouse models of TSC and ASD.…”

Insights into the structure and function of the hippocampus: implications for the pathophysiology and treatment of autism spectrum disorder

“…Tuberous sclerosis complex is a rare form of ASD that is often accompanied by epilepsy and cognitive deficits, caused by mutations in either of the Tuberous sclerosis complex 1 or 2 ( Tsc1/2 ) gene. These genes act as inhibitors of the mTOR signaling, and their mutations lead to hyperactivity of the pathway ( 130 ). Like other syndromic ASDs, tuberous sclerosis complex mice also have impairments in hippocampus-dependent spatial learning ( 131 – 133 ), contextual fear memory ( 131 – 133 ), and spatial working memory ( 131 ), associated with hippocampal synaptic excitation/inhibition imbalance induced by up-regulated mTORC1 signaling ( 131 , 134 ).…”